The prevalence of asthma has doubled in the past 3 decades and is now a major public health problem worldwide, particularly in westernized societies. While the precise mechanisms leading to the development of allergic asthma are not fully understood, the association between antigen-induced IgE production, bronchial inflammation and airway hyperreactivity (AHR) has been well documented. Consequently, inhaled corticosteroids (ICS) have become the first-line treatment for persistent asthma. ICS are not without adverse effects and many patients are reluctant to use them. In view of this, many physicians and patients have increasingly turned to complementary and alternative medicine for the treatment of asthma, despite the lack of well-controlled scientific studies demonstrating its benefits. Using a well characterized murine model of asthma, we have investigated a Chinese herbal preparation, MSSM-002, which is based on a traditional formula used at the Chinese-Japan Friendship Hospitalin Beijing, China. We found that MSSM-002, and more recently a modified preparation containing 3 herbs, ASHMI, could virtually eliminate airwayhyperreactivity, markedly reduce lung inflammation, mucus production and collagen formation, and reduce pulmonary and systemic Th2 responses in allergen-challenged mice. Given our preliminary studies and the long history of using all 3 herbs in this preparation in China, we investigatedthe efficacyand safety of ASHMI in 91asthmatics (ages 18-60) with persistent moderate-severe asthma in a randomized, double blind active-controlled study in collaboration with Dr. Ming Chun Wen, President of Weifang Asthma Hospital. The results showed that oral ASHMI significantly improved lung function and reduced symptom scores and serum IgE levels. No severe adverse effects were observed. In contrast to prednisone, ASHMI did not have negative effects on adrenal function and had a beneficial immunoregulatory effect on Th1/Th2 balance. Based on these preliminary studies, we hypothesize that ASHMI will be safe and effective in improving the outcome of asthma in atopic patients with moderate to severe asthma. In this project, we will conduct Phase l/ll clinical trials to assess the safety and therapeutic efficacy of ASHMI in the treatment of atopic patients with moderate tosevere persistent asthma. We have submitted an IND application (IND#71526 under review). Immunomodulatory effects in the lung will be assessed by comparing exhaled nitric oxide (eNO), inflammatory cell counts in induced sputum, and inflammatory markers in exhaled breath condensates in patients prior to and following 6 months of ASHMI / standard therapy. Systemic immunomodulatory effects will be determined by comparing allergen-specific mast cell and basophil histamine releasibility, and in vitro cytokine responses of peripheral blood mononuclear cells from allergic asthma patients prior to and following 6 months of ASHMI / standard therapy. In conjunction with other projects in this Center proposal, we should gain insight into the immunomodulatory effects of a novel therapeutic agent for the treatment of asthma.